DESCRIPTION: (from applicant's abstract): This program uses molecular, immunological, and clinical approaches for the development and cross-clade evaluation of an AIDS vaccine. Immunogens focus on the use of DNA priming followed by recombinant modified vaccinia Ankara (MVA) boosters to raise T as well as B cell responses. The program will be accomplished by a collaborative effort of scientists at Emory University, the National Institutes of Allergy and Infectious Diseases (NIAID), and the Centers for Disease Control (CDC.) The program builds on a preclinical trial of the Program Director in which DNA priming followed by recombinant pox virus boosters raised neutralizing antibody-independent containment of serial SHIV challenges. It also builds on on-going preclinical studies of program participants in which DNA priming, followed by MVA boosters, has raised high titer, multi-epitope T-cell responses. The program seeks support to develop and test in Phase 1 trials, two sets of HIV-1 immunogens: clade B immunogens representing viruses endemic in the United States, and clade AG immunogens representing the IbNG-like infections at the CDC test site in Abidjan, Cote d'Ivoire. Hypotheses address the impact of clade-specific as opposed to non-clade specific or mixed clade immunogens on cross-clade T-cell responses. Critical milestones include the evaluation of clade-specific sequences on cross-clade responses and the development of DNA immunogens or formulations that allow DNA to be used at micro gram rather than mg levels for priming. Three projects and two cores support the proposal. Project 1, "DNA and MVA Immunogens" will develop immunogens to allow the evaluation of cross-clade T-cell responses and increase the efficiency of DNA priming. Project 2, "Preclinical Trials" will evaluate DNAs or formulated DNAs in mouse and macaque models and provide safety and immunogenicity data to support INDs for Phase 1 clinical trials. Project 3, "Clinical Trials" will develop T-cell assays to measure vaccine responses in human trials, establish criteria for distinguishing vaccinated and infected humans, and conduct Phase 1 trials testing clade B and clade AG DNAJMVA vaccines singly and in combination.